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Treosulfan conditioning for allogeneic transplantation in multiple myeloma - improved overall survival in first line haematopoietic stem cell transplantation - a large retrospective study by the Chronic Malignancies Working Party of the EBMT
Gran, C., Wang, J., Nahi, H., Koster, L., Gahrton, G., Einsele, H., Niittyvoupio, R., Edinger, M., Beelen, D., Ciceri, F., et al
British journal of haematology. 2020
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Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3-Internal Tandem Duplication Mutation (SORMAIN)
Burchert, A., Bug, G., Fritz, L. V., Finke, J., Stelljes, M., Rollig, C., Wollmer, E., Wasch, R., Bornhauser, M., Berg, T., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020;:Jco1903345
Abstract
PURPOSE Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the FMS-like tyrosine kinase 3 gene (FLT3-ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT. PATIENTS AND METHODS In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with FLT3-ITD-positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first. RESULTS With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank P = .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank P = .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib. CONCLUSION Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for FLT3-ITD-positive AML.
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Second allogeneic stem cell transplantation in patients with acute lymphoblastic leukaemia: a study on behalf of the Acute Leukaemia Working Party of the European Society for Blood and Marrow Transplantation
Nagler, A., Labopin, M., Dholaria, B., Finke, J., Brecht, A., Schanz, U., Niittyvuopio, R., Neubauer, A., Bornhauser, M., Santarone, S., et al
British journal of haematology. 2019
Abstract
Although second allogeneic haematopoietic cell transplantation (allo-HCT2) is a therapeutic option for patients relapsing after first HCT (allo-HCT1), there is limited data on allo-HCT2 in patients with acute lymphoblastic leukaemia (ALL). We retrospectively studied 245 patients receiving allo-HCT2 as a salvage treatment for relapse following allo-HCT1 between the 2000 and 2017. The median age at allo-HCT2 was 34.6 years (range: 18-74). One hundred and one patients (41%) received sibling donor and 144 (59%) unrelated donor allo-HCT2. Acute graft-versus-host disease (GVHD) grade II-IV and III-IV occurred in 33% and 17% of the patients, respectively. The incidence of 2-year total and extensive chronic GVHD was 38% and 19%, respectively. The 2- and 5-year cumulative incidence of non-relapse mortality, relapse incidence, leukaemia-free survival, overall survival and GVHD-free, relapse-free survival (GRFS) were 24% and 26%, 56% and 62%, 20% and 12%, 30% and 14% and 12% & 7%, respectively. In multivariate analysis, factors associated with overall survival were age, time from allo-HCT1 to relapse, conditioning for allo-HCT1, Karnofsky score at allo-HCT2 and donor type for allo-HCT2. In conclusion, outcomes of allo-HCT2 in ALL patients were poor, with only 14% overall survival and 7% GRFS at 5 years with very high relapse incidence.
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Modified DHAP regimen in the salvage treatment of refractory or relapsed lymphomas
Kroschinsky, F., Rollig, D., Riemer, B., Kramer, M., Ordemann, R., Schetelig, J., Bornhauser, M., Ehninger, G., Hanel, M.
Journal of cancer research and clinical oncology. 2019
Abstract
BACKGROUND The combination of dexamethasone, high-dose cytarabine, and cisplatin (DHAP) is an established salvage regimen for lymphoma patients. We hypothesized that a modified administration schedule for cisplatin and cytarabine results in lower toxicity and improved efficacy. METHODS We retrospectively analysed 119 patients with relapsed or refractory, aggressive, or indolent B-cell lymphomas, mantle-cell lymphomas, peripheral T-cell lymphomas, or Hodgkin's lymphomas who were treated with the modified DHAP (mDHAP) regimen (dexamethasone 40 mg 15 min-i.v. infusion, days 1-4; cytarabine 2 x 0.5 g/m(2) 1 h-i.v. infusion, days 1-4; cisplatin 25 mg/m(2) 24 h-i.v. infusion, days 1-4). Responding and eligible patients underwent stem-cell transplantation. RESULTS In total, 185 treatment cycles were evaluable. Severe myelosuppression was the main toxicity occurring in 90% of the cycles. Febrile neutropenia or documented infection was found in less than 40%. Two patients died related to treatment (TRM, 1.7%). Nephrotoxicity did not exceed CTC grade 3, which occurred in four cycles only (2.2%). Complete (CR) or partial (PR) responses after mDHAP were documented in 16% and 39% (overall response rate 55%). Harvest of autologous stem cells was successful in 94 (79%) patients and 85 patients (71%) proceeded to stem-cell transplantation. The median overall and progression-free survival was 50.8 and 25.8 months. CONCLUSIONS An improvement in efficacy could not be observed after modified DHAP regimen; however, manageable toxicity and reduced renal complications suggest further investigation. The study, however, also underlines the need for new concepts in the management of advanced and high-risk lymphomas.
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Reduced intensity conditioning regimens including alkylating chemotherapy do not alter survival outcomes after allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia compared to low-intensity non-myeloablative conditioning
Andersen, N. S., Bornhauser, M., Gramatzki, M., Dreger, P., Vitek, A., Karas, M., Michallet, M., Moreno, C., van Gelder, M., Henseler, A., et al
Journal of cancer research and clinical oncology. 2019
Abstract
PURPOSE The optimal dose intensity for conditioning prior to allogeneic hematopoietic stem cell transplantation (alloHSCT) for chronic lymphocytic leukemia (CLL) is unknown. METHODS We retrospectively compared outcomes of patients who received a first alloHCST after non-myeloablative (NMA) and reduced intensity conditioning (RIC). Data of 432 patients with a median age of 55 years were included, of which 86 patients underwent NMA and 346 RIC. RESULTS The median follow-up after alloHSCT was 4.3 years. Compared to the RIC group, more NMA patients had purine-analog-sensitive disease, were in complete remission and received matched related donor transplantation. After RIC, the probabilities for 5-year OS, EFS, CIR, and NRM were 46%, 38%, 28%, and 35% and after NMA the respective probabilities were 52%, 43%, 25%, and 32%. In multivariate analysis, remission status prior to conditioning but not RIC versus NMA conditioning had a significant impact on CIR, EFS, and OS. CONCLUSION Presumed higher anti-leukemic activity of RIC versus NMA conditioning did not translate into better outcomes after alloHSCT, but better remission status prior to conditioning did. Effective pathway inhibitor-based salvage therapies combined with NMA conditioning might thus represent the most attractive contemporary approach for alloHSCT for patients with CLL.
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Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT
Noviello, M., Manfredi, F., Ruggiero, E., Perini, T., Oliveira, G., Cortesi, F., De Simone, P., Toffalori, C., Gambacorta, V., Greco, R., et al
Nature communications. 2019;10(1):1065
Abstract
The major cause of death after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for acute myeloid leukemia (AML) is disease relapse. We investigated the expression of Inhibitory Receptors (IR; PD-1/CTLA-4/TIM-3/LAG-3/2B4/KLRG1/GITR) on T cells infiltrating the bone marrow (BM) of 32 AML patients relapsing (median 251 days) or maintaining complete remission (CR; median 1 year) after HSCT. A higher proportion of early-differentiated Memory Stem (TSCM) and Central Memory BM-T cells express multiple IR in relapsing patients than in CR patients. Exhausted BM-T cells at relapse display a restricted TCR repertoire, impaired effector functions and leukemia-reactive specificities. In 57 patients, early detection of severely exhausted (PD-1(+)Eomes(+)T-bet(-)) BM-TSCM predicts relapse. Accordingly, leukemia-specific T cells in patients prone to relapse display exhaustion markers, absent in patients maintaining long-term CR. These results highlight a wide, though reversible, immunological dysfunction in the BM of AML patients relapsing after HSCT and suggest new therapeutic opportunities for the disease.
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7.
Graft-versus-host disease and graft-versus-leukaemia effects in secondary acute myeloid leukaemia: a retrospective, multicentre registry analysis from the Acute Leukaemia Working Party of the EBMT
Baron, F., Labopin, M., Savani, B. N., Beohou, E., Niederwieser, D., Eder, M., Potter, V., Kroger, N., Beelen, D., Socie, G., et al
British journal of haematology. 2019
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Editor's Choice
Abstract
We assessed the susceptibility of secondary acute myeloid leukaemia (sAML) to graft-versus-leukaemia effects. Data from 2414 sAML patients in first (n = 2194) or second (n = 220) complete remission were included. They were given grafts from human leucocyte antigen (HLA)-matched sibling (MSD, n = 1085), 10/10 unrelated donor (MUD, n = 1066) or 9/10 mismatched unrelated donor (MMUD, n = 263). The 100-day incidence of grade II-IV acute graft-versus-host disease (GVHD) was 25% while 2-year incidence of chronic GVHD was 38%. Relapse rates declined steadily by duration of follow-up and were significantly lower in patients with chronic GVHD (P < 0.001). Limited (hazard ratio [HR] = 0.66, P < 0.001) and extensive (HR = 0.52, P < 0.001) chronic GVHD were associated with a lower incidence of relapse. Each grade III-IV acute (HR = 7.04, P < 0.001) as well as limited (HR = 1.42, P = 0.03) and extensive (HR = 3.97, P < 0.001) chronic GVHD were associated with higher non-relapse mortality (NRM). This translated to better overall survival (OS; HR = 0.61, P < 0.001) in patients with limited chronic GVHD. In contrast, grade III-IV acute and extensive chronic GVHD were associated with worse OS (HR = 3.16, P < 0.001 and HR = 1.21, P = 0.03, respectively). Further, in comparison to HLA-identical sibling recipients, MUD recipients had a lower risk of relapse (HR = 0.82, P = 0.03) but higher NRM (HR = 1.38, P = 0.004). In conclusion, these data demonstrate that sAML is susceptible to graft-versus-leukaemia effects.
PICO Summary
Population
Patients with secondary acute myeloid leukaemia (sAML) (n=2414)
Intervention
Allo-transplant from human leucocyte antigen (HLA)-matched sibling (MSD, n = 1085), 10/10 unrelated donor (MUD, n = 1066) or 9/10 mismatched unrelated donor (MMUD, n = 263)
Comparison
None
Outcome
The 100-day incidence of grade II-IV acute graft-versus-host disease (GVHD) was 25% while 2-year incidence of chronic GVHD was 38%. Relapse rates declined steadily by duration of follow-up and were significantly lower in patients with chronic GVHD. Limited and extensive chronic GVHD were associated with a lower incidence of relapse. Each grade III-IV acute as well as limited and extensive chronic GVHD were associated with higher non-relapse mortality (NRM). This translated to better overall survival (OS) in patients with limited chronic GVHD. In contrast, grade III-IV acute and extensive chronic GVHD were associated with worse OS. Further, in comparison to HLA-identical sibling recipients, MUD recipients had a lower risk of relapse but higher NRM.
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Radioimmunotherapy in combination with reduced-intensity conditioning for allogeneic hematopoietic cell transplantation in patients with advanced multiple myeloma
Fasslrinner, F., Stolzel, F., Kramer, M., Teipel, R., Brogsitter, C., Morgner, A., Arndt, C., Bachmann, M., Hanel, M., Rollig, C., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Radioimmunotherapy (RIT) has the potential to reduce the incidence of relapse after allogeneic hematopoietic cell transplantation (allo-HCT) in patients with advanced-stage multiple myeloma (MM). In this study, we evaluated the efficacy of RIT in combination with chemotherapy-based reduced-intensity conditioning (RIC). RIT was based on the coupling of an anti-CD66 antibody to the beta emitter 188-rhenium (188-re) for targeted bone marrow irradiation. Between 2012 and 2018, 30 MM patients, most of them heavily pretreated including various therapies with proteasome inhibitors, immunomodulatory drugs, anti CD38 antibodies, and autologous hematopoietic cell transplantation (auto-HCT), were treated with a RIT-RIC combination prior to allo-HCT. In addition to a fludarabine plus melphalan- or treosulfan-based RIC a median dose of 18.1 Gy (interquartile range (IQR) 14.6 to 24.1) was applied to the bone marrow. After a median follow-up time for surviving patients of 2.1 years (IQR 1.3-3.0), the two-year progression-free survival and overall survival rates were 43 % (95% CI 26-73%) and 55 % (95% CI 38-79), respectively. The two-year non-relapse mortality and cumulative incidence of progression were 17% (95% CI 3-30%) and 46 % (95% CI 25-67%), respectively. Renal toxicity and mucositis were the most frequently observed extramedullary side effects. In conclusion, the addition of RIT to RIC was safe and feasible, and resulted in promising outcomes compared to those previously reported for RIC-based allo-HCT-treated relapsed/refractory MM patients without RIT addition. Nevertheless, in spite of RIT addition, relapse after allo-HCT remained a major determinant of therapeutic failure. Therefore, development of novel RIT strategies (e.g., dual targeting strategies or combinations with adapter chimeric antigen receptor T cell-based therapies) are warranted.
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Allogeneic haematopoietic cell transplantation offers the chance of cure for patients with transformed follicular lymphoma
Heinzelmann, F., Bethge, W., Beelen, D. W., Stelljes, M., Dreger, P., Engelhard, M., Finke, J., Kroger, N., Holler, E., Bornhauser, M., et al
Journal of cancer research and clinical oncology. 2018
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Editor's Choice
Abstract
PURPOSE In patients with follicular lymphoma, secondary transformation to aggressive lymphoma (tFL) implies a poor prognosis. In principle, allogeneic haematopoietic cell transplantation (allo-HCT) offers a chance of cure for tFL but is rarely practiced. Aim of this retrospective multicenter study was to define the actual significance of allo-HCT in treatment of tFL. METHODS The database of the German Registry for Stem Cell Transplantation (DRST) was screened for patients who underwent allo-HCT for tFL 1998-2008. Confirmation of tFL-diagnosis by local and/or pathologists of the National NHL Board was mandatory for enrolment. Gaps in reported EBMT Minimum Essential Data datasets (MED-A) were filled by local DRST data managers. Relevant HCT outcome variables were evaluated by uni- and multivariate statistical analysis. RESULTS Median age of enrolled 33 patients was 51 years with a post allo-HCT median follow-up of 7.1 years of surviving patients. At time of HCT 24/33 patients had chemosensitive disease. In 24/33 patients reduced intensity conditioning (RIC) was used. Estimated 1, 2, 5-year overall survival (OS) and event-free survival rates were 49/39/33, and 33/30/24%. Cumulative 100 days non-relapse mortality was 25%. Chemosensitive disease, RIC, and limited chronic GvHD were identified as independent prognostic factors for OS. CONCLUSIONS Allo-HCT offers the chance of cure for tFL.
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Enhanced labile plasma iron and outcome in acute myeloid leukaemia and myelodysplastic syndrome after allogeneic haemopoietic cell transplantation (ALLIVE): a prospective, multicentre, observational trial
Wermke, M., Eckoldt, J., Gotze, K. S., Klein, S. A., Bug, G., de Wreede, L. C., Kramer, M., Stolzel, F., von Bonin, M., Schetelig, J., et al
The Lancet. Haematology. 2018
Abstract
BACKGROUND The effect of systemic iron overload on outcomes after allogeneic haemopoietic cell transplantation (HCT) has been a matter of substantial debate. We aimed to investigate the predictive value of both stored (MRI-derived liver iron content) and biologically active iron (enhanced labile plasma iron; eLPI) on post-transplantation outcomes in patients with acute myeloid leukaemia or myelodysplastic syndrome undergoing allogenic HCT. METHODS The prospective, multicentre, observational, ALLogeneic Iron inVEstigators (ALLIVE) trial recruited patients at five centres in Germany. We enrolled patients with acute myeloid leukaemia or myelodysplastic syndrome undergoing allogeneic HCT. Patients underwent cytotoxic conditioning for a median of 6 days (IQR 6-7) before undergoing allogeneic HCT and were followed up for up to 1 year (+/-3 months) post-transplantation. eLPI was measured in serum samples with the FeROS eLPI kit (Aferrix, Tel-Aviv, Israel) and values greater than 0.4 mumol/L were considered to represent raised eLPI. Liver iron content was measured by MRI. The primary endpoints were the quantitative delineation of eLPI dynamics during allogeneic HCT and the correlation coefficient between liver iron content before HCT and dynamic eLPI (eLPIdyn; maximum eLPI minus baseline eLPI). All patients with available data were included in all analyses. This is the final analysis of this completed trial, which is registered with ClinicalTrials.gov, number NCT01746147. FINDINGS Between Dec 13, 2012, and Dec 23, 2014, 112 patients underwent allogeneic HCT. Liver iron content before allogeneic HCT was not significantly correlated with eLPIdyn (rho=0.116, p=0.22). Serum eLPI concentrations rapidly increased during conditioning, and most (79 [73%] of 108) patients had raised eLPI by the day of transplantation. Patients with a pretransplant liver iron content greater than or equal to 125 mumol/g had an increased incidence of non-relapse mortality (20%, 95% CI 14-26) compared with those with lower concentrations (7%, 2-12; p=0.039) at day 100. Patients who had raised eLPI at baseline also had a significantly increased incidence of non-relapse mortality at day 100 (33%, 15-52) compared with those who had normal eLPI at baseline (7%, 2-13; p=0.00034). INTERPRETATION eLPI is a possible biological mediator of iron-related toxicity. Peritransplantation eLPI-scavenging strategies could be explored in prospective interventional clinical trials for patients with systemic iron overload. FUNDING The Technical University of Dresden and Novartis.